The opioid enadoline has analgesia-related effects which are thought to involve its receptor-mediated actions. These actions also have been associated with unfavorable side-effects that may limit the clinical application of previously developed -opioids. The present studies were conducted to compare the behavioral effects of enadoline and other -opioids by examining their effects in a group of four squirrel monkeys trained to distinguish injections of enadoline (1.7 fg/kg, i.m.) from injections of saline. First, effects of opioids including enadoline, PD 117302, U50,488H, bremazocine, ethylketocyclazocine, GR 89686A, and (-)-spiradoline were studied in all monkeys. The effects of EMD 61753, a -agonist which penetrates the CNS poorly and (+)-spiradoline, the inactive enantiomer of (-)-spiradoline, also were determined in each subject. Subsequently, the effects of enadoline were redetermined in all monkeys after pretreatment with the opioid antagonist naltrexone. All drugs except (+)-spiradoline and the peripherally-active -opioid EMD 61753 produced dose-related increases in responding on the enadoline-associated lever and full substitution in all subjects. Pretreatment with naltrexone shifted the dose-effect function for enadoline to the right in a manner consistent with receptor-mediated antagonism. These results indicate that the behavioral effects of enadoline are mediated by its actions at receptors in the CNS and suggest that its behavioral effects in clinical settings might be comparable to those of other opioids.